Substituted N-heteroaryl-1,2-diaminocyclobutene-3,4-dione compounds

ABSTRACT

The compounds of the formula: ##STR1## wherein R 1  is hydrogen, straight or branched chain alkyl, cyclic or bicyclic alkyl, alkanoyl, alkylsulfonyl, aroyl, arylalkenoyl, arylsulfonyl, arylalkanoyl or arylalkylsulfonyl; R 2  is hydrogen, straight or branched chain alkyl or cyclic or bicyclic alkyl; A is selected from the following: ##STR2## wherein R 9  is hydrogen, alkyl, perfluoroalkyl, alkoxy, perfluoroalkoxy, amino, mono- or dialkylamino, alkylsulfonamido, alkylcarboxamido, nitro, cyano, carboxyl, chloro, bromo, fluoro or iodo; n is an integer from 0 to 6; R 3  and R 4 , independent from each other, are hydrogen, straight or branched chain alkyl, cyclic or bicyclic alkyl, perfluoroalkyl, hydroxyalkyl, alkoxyalkyl, fluoro, or, when taken together, form a spirocyclic ring; R 5  and R 6 , independent from each other, are selected from the following: cyano, nitro, amino, alkyl, perfluoroalkyl, alkoxy, perfluoroalkoxy, mono- or dialkylamino, sulfonamide, alkylsulfonamido, arylsulfonamido, alkylcarboxamido, arylcarboxamido, alkylsulfonyl, perfluoroalkylsulfonyl, arylsulfonyl, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl, carboalkoxy, hydroxyl, or hydrogen; and the pharmaceutically acceptable salts thereof relax smooth muscles.

This is a Division of application Ser. No. 08/334,475 filed Nov. 4, 1994now U.S. Pat. No. 5,466,712 issued Nov. 14, 1995.

BACKGROUND OF INVENTION

The present invention relates to novel 1, 2-diamino derivatives ofcyclobutene 3-4-diones having pharmacological activity, to a process fortheir preparation, to pharmaceutical compositions containing them, andto their use in the treatment of disorders associated with smooth musclecontraction; via potassium channel modulation. Such disorders include,but are not limited to: urinary incontinence, hypertension, asthma,premature labor, irritable bowel syndrome, congestive heart failure,angina, and cerebral vascular disease.

Stemp et al. disclose a class of amino substituted cyclobutenedionederivatives of chromans described as having blood pressure loweringactivity and bronchodilatory activity in EP-426379-A2. Several series of1-amino-2-phenylalkylamino-cyclobutene-3,4-diones are reported as H-2receptor antagonists by Algieri et al. in U.S. Pat. No. 4,390,701 andits numerous divisionals and CIPs. Several related1-amino-2-phenoxyalkylamino derivatives are disclosed by Nohara et al.in U.S. Pat. No. 4,673,747.

The syntheses of representative 1,2-diamino-cyclobutene-3,4-diones aredescribed in the following publications: Tietze et al., Chem Ber. 1991,124, 1215; Tietze et al., Bioconjugate Chem. 1991, 2, 148; Ehrhardt etal., Chem. Ber. 1977, 110, 2506, and Neuse et al., Liebigs Ann. Chem.1973, 619.

DESCRIPTION OF THE INVENTION

Accordingly, the present invention discloses compounds represented bythe formula (I): ##STR3## wherein:

R₁ is hydrogen, C₁₋₁₀ straight or branched chain alkyl, C₃₋₁₀ cyclic orbicyclic alkyl, alkanoyl of 2 to 7 carbon atoms, alkylsulfonyl of 1 to 7carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms;

R₂ is hydrogen, C₁₋₁₀ straight or branched chain alkyl or C₃₋₁₀ cyclicor bicyclic alkyl;

A is a substituted phenyl group of the following formula: ##STR4##wherein:

R₇ and R₈, independent from each other, are selected from the following:cyano, nitro, amino, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆perfluoroalkoxy, amino, C₁₋₁₂ mono- or dialkylamino, sulfonamide, C₁₋₆alkylsulfonamido, C₆₋₁₂ arylsulfonamido, C₁₋₆ alkylcarboxamido, C₆₋₁₂arylcarboxamido, C₁₋₆ alkylsulfonyl, C₁₋₆ perfluoroalkylsulfonyl, C₆₋₁₂arylsulfonyl, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl,carboalkoxy of 2 to 7 carbon atoms, hydroxyl or hydrogen;

or, A is Het where Het is selected from the following: ##STR5## wherein:

R₉ is hydrogen, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆perfluoroalkoxy, amino, C₁₋₁₂ mono- or dialkylamino. C₁₋₆alkylsulfonamido, C₁₋₆ alkylcarboxamido, nitro, cyano, carboxyl, chloro,bromo, fluoro, iodo;

n is an integer from 0 to 6;

R₃ and R₄ are, independent from each other, hydrogen, C₁₋₁₀ straight orbranched chain alkyl, or C₃₋₁₀ cyclic or bicyclic alkyl; C₁₋₁₀ perfluoroalkyl, C₁₋₁₀ hydroxyalkyl, C₁₋₁₀ alkoxyalkyl, fluoro; or, when takentogether, form a spirocyclic ring containing a total of 3-7 carbonatoms;

R₅ and R₆, independent from each other, are selected from the following:cyano, nitro, amino, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆perfluoroalkoxy, amino, C₁₋₁₂ mono- or dialkylamino, sulfonamide, C₁₋₆alkylsulfonamido, C₆₋₁₂ arylsulfonamido, C₁₋₆ alkylcarboxamido, C₆₋₁₂arylcarboxamido, C₁₋₆ alkylsulfonyl, C₁₋₆ perfluoroalkylsulfonyl, C₆₋₁₂arylsulfonyl, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl,carboalkoxy, hydroxyl, or hydrogen;

or a pharmaceutically acceptable salt thereof.

A preferred aspect of this invention includes compounds of formula (I)wherein:

R₁ and R₂ are as stated above;

A is a substituted phenyl group of the following formula: ##STR6##wherein:

R₇ and R₈, independent from each other, are selected from the following:cyano, nitro, amino, chloro, bromo, fluoro, iodo, 1-imidazolyl,carboxyl, hydrogen;

or A is Het where Het is selected from the following: ##STR7## wherein:

R₉ is as stated above;

n=0;

R₃ and R₄ are, independent from each other, hydrogen, C₁₋₁₀ straight orbranched chain alkyl, C₁₋₁₀ perfluoro alkyl, C₁₋₁₀ hydroxyalkyl orfluoro;

R₅ and R₆, independent from each other, are selected from the following:cyano, nitro, amino, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆perfluoroalkoxy, amino, chloro, bromo, fluoro, iodo, carboxyl,carboalkoxy, hydroxyl, hydrogen;

or a pharmaceutically acceptable salt thereof.

It is understood that the definition of the compounds of formula (I),when R₁, R₂, R₃, R₄, R₅, or R₆ contain asymmetric carbons, or when R₃ isdifferent from R₄, encompass all possible stereoisomers and mixturesthereof. In particular, it encompasses racemic modifications and opticalisomers. The optical isomers may be obtained in pure form by standardseparation techniques. The pharmaceutically acceptable salts are thosederived from such organic and inorganic acids as: lactic, citric,acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic,phosphoric, nitric, sulfuric, methanesulfonic, and similarly knownacceptable acids. Where R₃, R₄, R₅ or R₆ are carboxyl groups, salts ofthe compounds of this invention may be formed with bases such as alkalimetals (Na, K, Li) or the alkaline earth metals (Ca or Mg).

The acyl groups representing R₁ are derived from such acids as acetic,propionic, butyric, valeric, caproic, methanesulfonic-ethanesulfonic,benzoic, toluic, cinnamic, phenylsulfonic, phenylacetic, naphthylacetic,benzylsulfonic and the like.

The present invention also provides a process for the preparation of acompound of formula (I). More particularly, the compounds of formula (I)may be prepared by reacting a compound of formula (II): ##STR8## whereinX is defined as a suitably designed leaving group such as methoxy,ethoxy, isopropoxy, halogeno, or similar groups, with a compound offormula (III):

    A.sub.1--NHRa.sub.a                                        (III)

wherein A₁ is A, and Ra₁ is R₁, as defined hereinbefore or a group ofatoms convertible thereto, followed by treatment with a compound offormula (IV): ##STR9## wherein n is as described above and Ra₂, Ra₃,Ra₄, Ra₅, Ra₆ are R₂, R₃, R₄, R₅, R₆, respectively, as definedhereinbefore or a group of atoms convertible thereto, in a solvent suchas ethanol or methanol at elevated temperatures.

As mentioned previously, the compounds of formula (I) have been found torelax smooth muscle. They are therefore useful in the treatment ofdisorders associated with smooth muscle contraction, disorders involvingexcessive smooth muscle contraction of the urinary tract (such asincontinence), or of the gastrointestinal tract (such as irritable bowelsyndrome), asthma, and hair loss. Furthermore, the compounds of formula(I) are active as potassium channel activators which render them usefulfor treatment of peripheral vascular disease, congestive heart failure,stroke, anxiety, cerebral anoxia and other neurodegenerative disorders.

The present invention accordingly provides a pharmaceutical compositionwhich comprises a compound of this invention and a pharmaceuticallyacceptable carrier. In particular, the present invention provides apharmaceutical composition which comprises an effective amount of acompound of this invention and a pharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration.However, they may be adapted for other modes of administration, forexample parenteral administration for patients suffering from heartfailure.

In order to obtain consistency of administration, it is preferred thatcomposition of the invention is in the form of a unit dose. Suitableunit dose forms include tablets, capsules and powders in sachets orvials. Such unit dose forms may contain from 0.1 to 100 mg of a compoundof the invention and preferably from 2 to 50 mg. Still further preferredunit dosage forms contain 5 to 25 mg of a compound of the presentinvention. The compounds of the present invention can be administeredorally at a dose range of about 0.01 to 100 mg/kg or preferably at adose range of 0.1 to 10 mg/kg. Such compositions may be administeredfrom 1 to 6 times a day, more usually from 1 to 4 times a day.

The compositions of the invention may be formulated with conventionalexcipients, such as a filler, a disintegrating agent, a binder, alubricant, a flavoring agent and the like. They are formulated inconventional manner, for example, in a manner similar to that used forknown antihypertensive agents, diuretics and β-blocking agents.

The present invention further provides a compound of the invention foruse as an active therapeutic substance. Compounds of formula (I) are ofparticular use in inducing smooth muscle relaxation.

The present invention further provides a method of treating smoothmuscle disorders in mammals including man, which comprises administeringto the afflicted mammal an effective amount of a compound or apharmaceutical composition of the invention.

The following examples are presented to illustrate rather than limit themethods for production of representative compounds of the invention.

EXAMPLE 1

4-[3,4-Dioxo-2-((R)-1-Phenyl-Ethylamino)-Cyclobut-1-Enylamino]-Benzonitrile

Step 1)

Preparation of 4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile

4-Aminobenzonitrile (3.47 g, 29.4 mmol) was added to a solution of3,4-diethyoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in absoluteethanol (100 mL). The mixture was heated at reflux overnight. Themixture was cooled, and the resulting yellow precipitate was collectedby vacuum filtration. Yield: 2.60 g (37%): mp 218°-222° C.; ¹ H NMR(DMSO-d₆): δ11.07 (s, 1H), 7.81 (d, 2H), 7.56 (d, 2H), 4.79 (q, 2H),1.46 (t, 3H).

Step 2)

Preparation of 4-[3,4-dioxo-2-((R)-1-phenyl-ethylamino)-cyclobut-1-enylamino]-benzonitrile

To the above squarate (0.50 g, 2.06 mmol) in ethanol (10 mL) was added(R)-α-methylbenzylamine (0.27 mL, 2.1 mmol). The mixture was heated atreflux for 16 hours and vacuum filtered. The precipitate wasrecrystallized from methanol to afford 0.17 g (26%) of product as a paleyellow solid: mp 273°-274° C.; [α]²⁵ _(D) -53.20 (DMSO); ¹ H NMR(DMSO-d₆): δ 9.91 (s, 1H), 8.2 L(d, 1H), 7.72 (d, 1H), 7.79-7.31 (m,9H), 5.29 (m, 1H), 1.59 (d, 3H). IR (KBr): 3200, 2230, 1790, 1670, 1600cm⁻¹ ; MS (m/z) 317 (M⁺).

Elemental analysis for C₁₉ H₁₅ N₃ O₂ Calc'd: C, 71.91; H, 4.76; N,13.24. Found: C, 71.26; H, 4.86; N, 13.49.

EXAMPLE 2

3-(5-Bromo-Pyridin-3-Ylamino)-4-((R)-1-Phenyl-Ethylamino)-Cyclobut-3-Ene-1,2-Dione

Step 1)

Preparation of3-(5-bromo-pyridin-3-ylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione)

3-Amino-5-bromopyridine (1.92 g, 11.3 mmol) was added to a solution of3,4-diethoxy-3-cyclobutene-1,2-dione (2.24 g, 11.1 mmol) in absoluteethanol (30 mL). The mixture was heated at reflux for 18 hours, cooledand filtered. The filtrate was concentrated and the resulting residuechromatographed (CH₃ OH/CH₂ Cl₂) to afford 2.06 g (62%) of product as anoff-white solid: ¹ H NMR (DMSO-d₆): δ 11.00 (s, 1H), 8.56 (s, 1H), 8.42(s, 1H), 8.09 (s, 1H), 4.79 (q, 2H), 1.42 (t, 3H).

Step 2)

Preparation of3-(5-Bromo-pyridin-3-ylamino)-4-((R)-1-phenyl-ethylamino)-cyclobut-3-ene-1,2-dione

To the above squarate (0.815 g, 2.74 mmol) in ethanol (25 mL) was added(R)-α-methylbenzylamine (0.36 mL, 2.8 mmol). The mixture was heated atreflux for 23 hours. The precipitate was filtered off and rinsed withethanol to afford 0.92 g (90%) of product as an off-white solid: mp268°-271° C. (dec); [α]²⁵ _(D) +6.57 (DMSO); ¹ H NMR (DMSO-d₆): δ 9.85(s, 1H), 8.44-8.15 (m, 4H), 7.43-7.27 (m, 5H), 5.29 (m, 1H), 1.59 (d,3H). IR (KBr): 3200, 1790, 1670, 1590 cm⁻ ; MS (m/z) 372 (MH⁺).

Elemental analysis for C₁₇ H₁₄ BrN₃ O₂ Calc'd: C, 54.86; H, 3.79; N,11.29. Found: C, 54.88; H, 3.67; N, 11.20.

EXAMPLE 3

3-(2-Methoxy-5-Trifluoromethyl-Phenylamino)-4-((R)-1-Phenyl-Ethylamino)-Cyclobut-3-Ene-1.2-Dione

Step 1)

Preparation of3-ethoxy-4-(2-methoxy-5-trifluoromethyl-phenylamino)-cyclobut-3-ene-1,2-dione

2-Methoxy-5-trifluoromethylaniline (5.62 g, 29.4 mmol) was added to asolution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) inabsolute ethanol (100 mL). The mixture was heated at reflux for 66 hour,cooled and filtered. The precipitate was purified by chromatography (CH₃OH/CH₂ Cl₂) to afford 1.88 g (20%) of product as a yellow solid: ¹ H NMR(DMSO-d₆): δ 10.42 (s, 1H), 7.64-7.20 (m, 3H), 4.69 (q, 2H), 3.90 (s,3H), 1.34 (t, 3H).

Step 2) Preparation of3-(2-methoxy-5-trifluoromethyl-phenylamino)-4-((R)-1-phenyl-ethylamine)-cyclobut-3-ene-1,2-dione

To the above squarate (0.806 g, 2.56 mmol) in ethanol (10 mL) was added(R)-α-methylbenzylamine (0.33 mL, 2.6 mmol). The mixture was heated atreflux for 23 hours. The clear yellow solution was concentrated and theresulting foam purified by chromatography (CH₃ OH/CH₂ Cl₂)to afford 0.84g (84%) of product as a white solid: mp 115°-124° C.; [α]²⁵ _(D) -33.61(DMSO); ¹ H NMR (DMSO-d₆): a 9.37 (s, 1H), 8.72 (d, 1H), 8.24 (s, 1H),7.42-7.19 (m, 7H), 5.33 (m, 1H), 3.97 (s, 1H), 1.59 (d, 3H). IR (KBr):3250, 1790, 1690, 1610 cm⁻¹ ; MS (m/z) 391 (MH⁺).

Elemental analysis for C₂₀ H₁₇ F₃ N₂ O₃ Calc'd: C, 61.54; H, 4.39; N,7.18. Found: C, 61.42; H, 4.26; N, 7.23.

EXAMPLE 4

3-((R)-1-Phenyl-Ethylamino)-4-(Pyridin-4-Ylamino)-Cyclobut-3-ene-1,2-Dione

Step 1)

Preparation of 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4mmol) in ethanol (100 mL) was added a suspension of 4-aminopyridine(2.77 g, 29.4 mmol) in ethanol (50 mL). The reaction mixture was heatedat reflux for 4 hours. Concentration and chromatography (EtOAc) of theresulting residue afforded 0.632 g (10%) of product as a white solid: ¹H NMR (DMSO-d₆): δ 11.18 (br s, 1H), 8.45 (d, 2H), 7.40 (d, 2H), 4.80(q, 2H), 1.43 (t, 3H).

Step 2) Preparation of3-((R)-1-phenyl-ethylamino)-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione

To the above squarate (0.850 g, 3.90 mmol) in ethanol (25 mL) was added(R)-α-methylbenzylamine (0.51 mL, 4.0 mmol). The mixture was heated atreflux for 23 hours. The precipitate was filtered off and rinsed withethanol. Chromatography (CH₃ OH/CH₂ Cl₂) afforded 0.276 g (24%) ofproduct as an off-white solid: mp 252°-254° C. (dec); [α]²⁵ _(D) -31.45(DMSO); ¹ H NMR (DMSO-d₆): δ 9.82 (s, 1H), 8.40 (d, 2H), 8.22 (d, 1H),7.45-7.38 (m, 7H), 5.28 (m, 1H), 1.59 (d, 3H). IR (KBr): 3200, 1800,1675, 1590 cm⁻¹ ; MS (m/z) 293 (MH⁺).

Elemental analysis for C₁₇ H₁₅ N₃ O₂ Calc'd: C, 69.61; H, 5.15; N,14.33. Found: C, 69.49; H, 5.06; N, 14.18.

EXAMPLE 5

4-[3,4-Dioxo-2-((S)-1-Phenyl-Ethylamino)-Cyclobut-1-Enylamino]-Benzonitrile

To the squarate of Example 1, step 1 (0.50 g, 2.06 mmol) in ethanol (10mL) was added (S)-α-methylbenzylamine (0.27 mL, 2.1 mmol). The mixturewas heated at reflux for 16 hours and vacuum filtered. The precipitatewas recrystallized from methanol to afford 0.17 g (26%) of product as apale yellow solid: mp 269°-270° C.; [α²⁵ _(D) +46.47 (DMSO); ¹ H NMR(DMSO-d₆): δ 9.91 (s, 1H), 8.21 (d, 1H), 7.72 (d, 1H), 7.79-7.31 (m,9H), 5.29 (m, 1H), 1.59 (d, 3H). IR (KBr): 3200, 2230, 1790, 1670, 1600cm⁻¹ ; MS (m/z) 317 (M⁺). Elemental analysis for C₁₉ H₁₅ N₃ O₂ Calc'd:C, 71.91; H, 4.76; N, 13.24. Found: C, 71.17; H, 4.83; N, 13.34.

EXAMPLE 6

3-(4-Trifluoromethoxy-Phenylamino)-4-((R)(-)-1-Phenyl-Ethylamino)-Cyclobut-3-Ene-1,2-Dione

Step 1)

Preparation of3-ethoxy-4-(4-trifluoromethoxy-phenylamino)-cyclobut-3-ene-1,2-dione

4-Trifluoromethoxyaniline (5.00 g, 28.2 mmol) was added to a solution of3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in absoluteethanol (50 mL). The mixture was heated at reflux overnight, then vacuumfiltered hot. The filtrate was reduced in volume and the resultingprecipitate was filtered to afford 4.50 g (53%) of white solid: mp145°-146° C.; ¹ H NMR (DMSO-d₆): δ 10.87 (s, 1H), 7.45 (d, 2H), 7.36 (d,2H), 4.75 (q, 2H), 1.41 (t, 3H).

Step 2)

Preparation of3-(4-trifluoromethoxy-phenylamino)-4-((R)-1-phenyl-ethylamine)-cyclobut-3-ene-1,2-dione

To the above squarate (0.330 g, 1.10 mmol) in ethanol (25 mL) was added(R)-α-methylbenzylamine (0.135 mg, 1.11 mmol). The reaction was refluxedfor 23 hours. Upon cooling, the product precipitated as a white solid0.350 g (84%): mp 258°-260° C.; [α]²⁵ _(D) -17.52 (DMSO); ¹ H NMR(DMSO-d₆): δ 9.70 (s, 1H), 8.12 (d, 1H), 7.51-7.28 (m, 9H), 5.28 (m,1H), 1.59 (d, 3H). IR (KBr): 3250, 1800, 1675, 1600 cm⁻¹ ; MS (m/z) 377(MH⁺).

Elemental analysis for C₁₉ H₁₅ F₃ N₂ O₃ Calc'd: C, 60.64; H, 4.02; N,7.44. Found: C, 60.40; H, 4.01; N, 7.21.

EXAMPLE 7

(R)-4-{2-[1-(4-Nitro-Phenyl)-Ethylamino]-3,4-Dioxo-Cyclobut-1-Enylamino}-Benzonitrile

To the squarate of Example 1, step 1 (0.598 g, 2.47 mmol) in ethanol (50mL) was added (R)-α-methyl-4-nitrobenzylamine hydrochloride (0.50 g, 2.5mmol) and N,N-diisopropylethylamine (0.43 g, 2.5 mmol). The mixture washeated at reflux for 16 hours. After cooling the precipitate wasfiltered off to afford 0.70 g (78%) of product as an orange solid: mp290°-295° C.; [α]²⁵ _(D) -100.52 (DMSO); ¹ H NMR (DMSO-d₆): δ 9.98 (s,1H), 8.32 (d, 1H), 8.25 (d, 2H), 7.79 (d, 2H), 7.68 (d, 2H), 7.57 (d,2H), 5.42 (m, 1H), 1.61 (d, 3H). IR (KBr): 3200, 2220, 1790, 1670, 1600cm⁻¹ ; MS (m/z) 362 (M⁺).

Elemental analysis for C₁₉ H₁₄ N₄ O₄ Calc'd: C, 62.98; H, 3.89; N,15.46. Found: C, 62.38; H, 3.73; N, 14.95.

EXAMPLE 8

3-[3,4-Dioxo-2-((R)-1-Phenyl-Ethylamino)-Cyclobut-1-Enylamino]-Benzonitrile

Step 1)

Preparation of 3-(3,4-dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile

3-Aminobenzonitrile (2.06 g, 17.4 mmol) was added to a solution of3,4-diethoxy-3-cyclobutene-1,2-dione (2.97 g, 17.5 mmol) in absoluteethanol (50 mL). The mixture was heated at reflux overnight. The mixturewas cooled and the resulting yellow precipitate was collected by vacuumfiltration. Yield: 3.40 g (81%): ¹ H NMR (DMSO-d₆): δ 10.95 (s, 1H),7.75-7.40 (m, 4H), 4.73 (q, 2H), 1.39 (t, 3H).

Step 2)

Preparation of3-[3,4-dioxo-2-((R)-1-phenyl-ethylamino)-cyclobut-1-enylamino]-benzonitrile

To the above squarate (1.00 g, 4.13 mmol) in ethanol (100 mL) was added(R)-α-methylbenzylamine (0.53 mL, 4.1 mmol). The mixture was heated atreflux overnight and vacuum filtered. The precipitate was trituratedtwice with hot methanol to afford 0.80 g (61%) of product as a paleyellow solid: mp 289°-290° C. (dec); [α]²⁵ _(D) -13.9 (DMSO); ¹ H NMR(DMSO-d₆): δ 9.72 (s, 1H), 8.25 (d, 1H), 7.90-7.28 (m, 9H), 5.30 (m,1H), 1.60 (d, 3H). IR (KBr): 3200, 2220, 1790, 1650, 1600 cm⁻¹ ; MS(m/z) 317 (M⁺).

Elemental analysis for C₁₉ H₁₅ N₃ O₂ Calc'd: C, 71.91; H, 4.76; N,13.24. Found: C, 71.80; H, 4.61; N, 13.33.

EXAMPLE 9

4-[3,4-Dioxo-2-(1-Methyl-1-Phenyl-Ethylamino)-Cyclobut-1-Enylamino]-Benzonitrile

To the squarate of Example 1, step 1 (0.81 g, 3.3 mmol) in ethanol (30mL) was added α,α-dimethylbenzylamine (0.45 g, 3.3 mmol). The mixturewas heated at reflux for 20 hours. After cooling the precipitate wasfiltered off and chromatographed (CH₃ OH/CH₂ Cl₂) to afford 0.41 g (37%)of product as yellow solid: mp>300° C.; ¹ H NMR (DMSO-d₆): δ 10.08 (s,1H), 8.38 (s, 1H), 7.79 (d, 2H), 7.61 (d, 2H), 7.48-7.27 (m, 5H), 1.78(s, 6H). IR (KBr): 3200, 2230, 1790, 1675, 1600 cm⁻¹ ; MS (m/z) 331(M⁺).

Elemental analysis for C₂₀ H₁₇ N₃ O₂.(0.1 CH₃ OH).(0.05 CH₂ Cl₂) Calc'd:C, 71.43; H, 5.21; N, 12.40. Found: C, 71.30; H, 5.33; N, 12.69.

EXAMPLE 10

4-[3,4-Dioxo-2-((R)-1-Phenyl-Propylamino)-Cyclobut-1Enylamino-Benzonitrile

To the squarate of Example 1, step 1 (1.79 g, 7.39 mmol) in ethanol (30mL) was added (R)-1-phenyl-propylamine (1.00 g, 7.40 mmol). The mixturewas heated at reflux for 18 hours, cooled slightly and vacuum filteredto afford 1.76 g (72%) of product as a yellow solid: mp 242°-243° C.;[α]²⁵ _(D) -52.73 (DMSO); ¹ H NMR, (DMSO-d₆): δ 9.84 (s, 1H), 8.12 (brd, 1H), 7.76 (d, 2H), 7.56 (d, 2H), 7.42-7.27 (m, 5H), 5.06 (m, 1H),1.94 (m, 2H), 0.90 (t, 3H). IR (KBr): 3200, 2220, 1790, 1670, 1600 cm⁻¹; MS (m/z) 331 (M⁺).

Elemental analysis for C₂₀ H₁₇ N₃ O₂ Calc'd: C, 72.49; H, 5.17; N,12.68. Found: C, 72.42; H, 5.01; N, 12.73.

EXAMPLE 11

4-[3,4-Dioxo-2-((S)-1-Phenyl-Propylamino)-Cyclobut-1-Enylamino]-Benzonitrile

To the squarate of Example 1, step 1 (1.79 g, 7.39 mmol) in ethanol (30mL) was added (S)-1-phenyl-propylamine (1.00 g, 7.40 mmol). The mixturewas heated at reflux for 18 hours, cooled slightly and vacuum filteredto afford 1.61 g (66%) of product as a yellow solid: mp 241°-243° C.;[α]²⁵ _(D) +52.33 (DMSO); ¹ H NMR (DMSO-d₆): δ 9.84 (s, 1H), 8.21 (br d1H), 7.76 (d, 2H) 7.56 (d, 2H), 7.42-7.27 (m, 5H), 5.06 (m, 1H), 1.94(m, 2H), 0.90 (t, 3H). IR (KBr): 3200, 2220, 1790, 1670, 1600 cm⁻¹ ; MS(m/z) 331 (M⁺).

Elemental analysis for C₂₀ H₁₇ N₃ O₂ Calc'd: C, 72.49; H, 5.17; N,12.68. Found: C, 72.17; H, 5.04; N, 12.80.

EXAMPLE 12

4-[3.4-Dioxo-2-(Benzylamino)-Cyclobut-1-Enylamino]-Benzonitrile

To the squarate of Example 1, step 1 (1.00 g, 4.13 mmol) in ethanol (30mL) was added benzylamine (0.45 mL, 4.1 mmol). The mixture was heated atreflux for 18 hours, cooled slightly and vacuum filtered. Theprecipitate was triturated with hot methanol to afford 0.78 g (62%) ofproduct as yellow solid: mp 288°-290° C. (dec); ¹ H NMR (DMSO-d₆): δ9.91 (s, 1H), 8.10 (m, 1H), 7.79 (d, 2H), 7.75 (d, 2H), 7.55 (d,2H),7.91-7.78(m, 5H),4.82(d, 2H). IR(KBr): 3190, 2220, 1790, 1660,1575cm⁻¹ ; MS (m/z) 303 (M⁺).

Elemental analysis for C₁₈ H₁₃ N₃ O₂ Calc'd: C, 71.28; H, 4.32; N,13.85. Found: C, 71.07; H, 4.16; N, 12.89.

EXAMPLE 13

(R)-4-{2-[1-(4-Methyl-Phenyl)-Ethylamino]-3,4-Dioxo-Cyclobut-1-Enylamino}-Benzonitrile

To the squarate of Example 1, step 1 (1.00 g, 4.13 mmol) in ethanol (30mL) was added (R)-1-(p -tolyl)-ethylamine (0.56 g, 4.1 mmol). Themixture was heated at reflux for 18 hours, cooled slightly and vacuumfiltered to afford 1.02 g (75%) of product as a yellow solid: mp>300°C.; [α]²⁵ _(D) -56.01 (DMSO); ¹ H NMR (DMSO-d₆): δ 9.81 (s, 1H), 8.10(m, 1H), 7.76 (d, 2H), 7.5.5 (d, 2H), 7.29 (d, 2H), 7.19 (d, 2H), 5.26(m, 1H), 1.57 (d, 3H). IR (KBr): 3200, 2220, 1790, 1670, 1600 cm⁻¹ ; MS(m/z) 331 (M⁺).

Elemental analysis for C₂₀ H₁₇ N₃ O₂ Calc'd: C, 72.49; H, 5.17; N,12.68. Found: C, 72.42; H, 5.07; N, 12.82.

EXAMPLE 14

(R)-4-{2-[1-(4-Methoxy-Phenyl)-Ethylamino]-3,4-Dioxo-Cyclobut-1-Enylamino}-Benzonitrile

To a solution of (1R,1'R)-N-(1'-phenylethyl)-1-(4"-methoxyphenyl)-ethylamine (1.37 g, 5.36mmol; prepared as in J. Med Chem. 1992, 35, 2327) and ammonium formate(1.01 g, 16.0 mmol) in methanol (125 mL) was added 10% palladium onactivated carbon. The suspension was refluxed for 2 h, filtered throughCelite and concentrated. The squarate of Example 1, step 1 (1.00 g, 4.13mmol) was added to a solution of the resulting residue in ethanol (30mL). The mixture was heated at reflux for 18 h, cooled slightly andvacuum filtered. The precipitate was chromatographed (CH₃ OH/CH₂ Cl₂)and recrystallized (CH₃ OH/CH₂ Cl₂) to afford 0.21 g (15%) of product asa yellow solid: mp>300° C.; [α]²⁵ _(D) -46.95 (DMSO); ¹ H NMR (DMSO-d₆):δ 9.89 (s, 1H), 8.13 (d, 1H), 7.77 (d, 2H), 7.56 (d, 2H), 7.34 (d, 2H),6.95 (d, 2H), 5.23 (m, 1H), 3.73 (s, 3H), 1.57 (d, 3H). IR (KBr): 3200,2200, 1800, 1670, 1575 cm⁻¹ ; MS (m/z) 347 (M⁺).

Elemental analysis for C₂₀ H₁₇ N₃ O₃.(0.03 CH₂ Cl₂) Calc'd: C, 68.75; H,4.91; N, 12.01. Found: C, 68.40; H, 4.74; N, 11.89.

EXAMPLE 15

(R)-4-{3,4-Dioxo-2-[1-(4-Trifluoromethoxy-Phenyl)-Ethylamino]-Cyclobut-1-Enylamino}-Benzonitrile

To a solution of (1R,1'R)-N-(1'-phenylethyl)-1-(4"-trifluoromethoxyphenyl)ethylamine (1.92 g,6.21 mmol; prepared as in J. Med Chem. 1992, 35, 2327) and ammoniumformate (1.17 g, 18.6 mmol) in methanol (150 mL) was added 10% palladiumon activated carbon. The suspension was refluxed for 2 h, filteredthrough Celite and concentrated. The squarate of Example 1, step 1 (1.00g, 4.13 mmol) was added to a solution of the resulting residue inethanol (35 mL). The mixture was heated at reflux for 18 h, cooledslightly and vacuum filtered. The precipitate was combined with a secondcrop of solid obtained from the cooled filtrate, chromatographed (CH₃OH/CH₂ Cl₂) and recrystallized (CH₃ OH/CH₂ Cl₂) to afford 0.74 g (45%)of product as a white solid: mp 281°-284° C. (dec); [α]²⁵ _(D)-55.94(DMSO); ¹ H NMR (DMSO-d₆): δ 9.94 (s, 1H), 8.22 (d, 1H), 7.78 (d,2H), 7.60-7.51. (m, 4H), 7.40 (d, 2H), 5.33 (m, 1H), 1.60 (d, 3H). IR(KBr): 3200, 2200, 1800, 1670, 1560 cm⁻¹ ; MS (m/z) 401 (M⁺).

Elemental analysis for C₂₀ H₁₄ F₃ N₃ O₃ Calc'd: C, 59.85; H, 3.52; N,10.47. Found: C, 59.94; H, 3.38; N, 10.43.

EXAMPLE 16

4-[3,4-Dioxo-2-(2,2,2-Trifluoro-1-Phenyl-Ethylamino)-Cyclobut-1-Enylamino]-Benzonitrile

To a solution of N-2,2,2-trifluoro-1-phenylethyl-N-1'-(phenyl)ethylamine(1.65 g, 6.22 mmol; prepared as in J. Org. Chem. 1977, 42, 2436) andammonium formate (1.17 g, 18.6 mmol) in methanol (150 mL) was added 10%palladium on activated carbon. The suspension was refluxed for 4 h,filtered through Celite and concentrated to a volume of approximately 10mL. The squarate of Example 1, step 1 (1.00 g, 4.13 mmol) and ethanol(20 mL) were added and the mixture was heated at reflux for 18 h, cooledslightly and vacuum filtered to remove a small amount of solid. Thefiltrate was chromatographed (CH₃ OH/CH₂ Cl₂) and the resulting yellowsolid crystallized from chloroform and ether to afford 0.72 g (47%) ofproduct as a pale yellow solid: mp 206°-207° C.; ¹ H NMR (DMSO-d₆): δ9.99 (s, 1H), 8.88 (d, 1 H), 7.82 (d, 2H), 7.60-7.46 (m, 9H), 5.98 (m,1H), 3.73 (s, 3H). IR (KBr): 3200 2200, 1800, 1690, 1570 cm⁻¹ ; MS (m/z)371 (M⁺).

Elemental analysis for C₁₉ H₁₂ F₃ N₃ O₂ Calc'd: C, 61.46; H, 3.26; N,11.32. Found: C, 61.26; H, 3.16; N, 11.23.

EXAMPLE 17

(R)-4-[3,4-Dioxo-2-(Phenyl-Ethylamino)-Cyclobut-1-Enylamino]-3-Methyl-Benzonitrile

Step 1)

Preparation of4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-3-methylbenzonitrile

4-Amino-3-methylbenzonitrile (1.94 g, 14.7 mmol) was added to a solutionof 3,4-diethoxy-3-cyclobutene-1,2-dione (2.53 g, 14.9 mmol) inacetonitrile (5 mL). After refluxing the mixture for 24 h a secondportion of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.15 g, 6.76 mmol) wasadded and heating was continued for an additional 48 h. The reactionmixture was diluted with ethyl acetate (50 mL), stirred vigorously andfiltered free of undissolved solid. The filtrate was chromatographed(CH₃ OH/CH₂ Cl₂) to afford 0.90 g (24%) of product as a yellow solid: ¹H NMR (DMSO-d₆): δ 10.50 (s, 1H), 7.76-7.63 (m, 2H), 7.31 (d, 1H), 4.71(q, 2H), 2.33 (s, 3H), 1.38 (t, 3H).

Step 2)

Preparation of(R)-4-[3,4-Dioxo-2-(1-phenyl-ethylamino)-cyclobut-1-enylamino]-3-methyl-benzonitrile

To the above squarate (0.90 g, 3.51 mmol) in ethanol (40 mL) was added(R)-α-methylbenzylamine (0.45 mL, 3.49 mmol). The mixture was heated atreflux for 18 h. The resulting clear solution solution was concentratedand the residue chromatographed (CH₃ OH/CH₂ Cl₂) to afford 0.98 g (85%)of product as a yellow solid: mp 110°-130° C. (dec); [α]²⁵ _(D) -40.91(DMSO) ¹ H NMR (DMSO-d₆): δ 8.95 (s, 1H), 8.58 (d, 2H), 7.70-7.28 (m,8H), 5.36 (m, 1H), 2.33 (s, 3H), 1.61 (d, 3H), IR (KBr): 3250, 2220,1790, 1690, 1590 cm⁻¹ ; MS (m/z) 332 (MH⁺).

Elemental analysis for C₂₀ H₁₇ N₃ O₂.(0.10 CH₂ Cl₂) Calc'd: C, 71.03; H,5.10; N, 12.36. Found: C, 71.37; H, 5.09; N, 12.61.

EXAMPLE 18

(R)-4-[3,4-Dioxo-2-(Phenyl-Ethylamino)-Cyclobut-1-Enylamino]-3-Ethyl-Benzonitrile

Step 1)

Preparation of4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-3-ethyl-benzonitrile

4-Amino-3-ethylbenzonitrile (2.00 g, 13.7 mmol) was added to a solutionof 3,4-diethoxy-3-cyclobutene-1,2-dione (2.30 g, 13.5 mmol) inacetonitrile (5 mL). After refluxing the mixture for 24 h a secondportion of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.15 g, 6.76 mmol) wasadded and heating was continued for an additional 24 h. The reactionmixture was diluted with ethyl acetate (45 mL), stirred vigorously andfiltered free of undissolved solid. The filtrate was concentrated andthe resulting residue was purified by chromatographed (CH₃ OH/CH₂ Cl₂)and trituration with ether to afford 0.86 g (24%) of product as a lightyellow solid: ¹ H NMR (DMSO-d₆): δ 10.57 (s, 1H), 7.77-7.66 (m, 2H),7.31 (d, 1H), 4.71 (q, 2H), 2.73 (q, 2H), 1.37 (t, 3H), 1.13 (t, 3H).

Step 2)

Preparation of(R)-4-[3,4-Dioxo-2-(1-phenyl-ethylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile

To the above squarate (0.85 g, 3.14 mmol) in ethanol (25 mL) was added(R)-α-methylbenzylamine (0.41 mL, 3.18 mmol). The mixture was heated atreflux for 18 h, cooled slightly and suction filtered. The filtrate wascooled by gradual evaporation of solvent and the precipitate whichformed was collected in two crops to afford 0.76 g (70%) of product asan off-white solid: mp 206°-207° C. (dec); [α]²⁵ _(D) -45.25 (DMSO); ¹ HNMR (DMSO-d₆): δ 9.98 (s, 1H), 8.55 (d, 2H), 7.68-7.29 (m, 8H), 5.37 (m,1H), 2.69 (q, 2H), 1.61 (d, 3H), 1.20 (t, 3H). IR (KBr): 3200, 2200,1800, 1670, 1570 cm⁻¹ ; MS (m/z) 345 (M⁺).

Elemental analysis for C₂₁ H₁₉ N₃ O₂ Calc'd: C, 73.03; H, 5.54; N,12.17. Found: C, 72.69; H, 5.52; N, 12.18.

EXAMPLE 19

(R)-N-(4-Cyano-Phenyl)-N-[3,4-Dioxo-2-(1-Phenyl-Ethylamino)-Cyclobut-1-Enyl-Acetamide

To a stirred solution of the squarate of Example 1, step 2 (1.77 g, 5.58mmol) in N,N-dimethylformamide (50 mL) was added, in one portion, sodiumhydride (as a 60% dispersion in mineral oil; 0.252 g, 6.30 mmol). Thefrothy suspension was stirred at rt for 15 min and then at 0° C. for anadditional 1 h. Acetic anhydride (0.58 mL, 6.15 mmol) was added and thereaction mixture was stirred at 0° C. for 1.5 h and then allowed to warmto rt. After an additional 1 h of stirring the reaction solution wasconcentrated. The resulting yellow solid was washed with successiveportions of acetone, methylene chloride and ethyl acetate. The combinedwashings were concentrated and the resulting residue chromatographed toafford 0.48 g (24%) of product as an off-white solid: mp 240°-243° C.;[α]²⁵ _(D) -94.66 (DMSO); ¹ H NMR (DMSO-d₆): δ 8.29 (d, 1H), 7.96 (d,2H), 7.69 (d, 2H), 7.45-7.25 (m, 5H), 5.49 (m, 1H), 2.06 (s, 3H), 1.59(d, 3H). IR (KBr): 3340, 2230, 1800, 1740, 1690, 1610 cm⁻¹ ; MS (m/z)359 (M⁺).

Elemental analysis for C₂₁ H₁₇ N₃ O₃.(0.05 CH₂ Cl₂) Calc'd: C, 69.53; H,4.74; N 11.56. Found: C, 69.16; H, 4.74; N, 11.53.

Smooth muscle relaxing activity of the compounds of this invention wasestablished in accordance with standard pharmaceutically accepted testprocedures in representative compounds as follows:

Sprague-Dawley rats (150-200 g) are rendered unconscious by CO₂asphyxiation and then euthanized by cervical dislocation. The bladder isremoved into warm (37 deg. C) physiological salt solution (PSS) of thefollowing composition (mM): NaCl, 118.4; KCl, 4.7; CaCl₂, 2.5; MgSO₄,4.7; H₂ O, 1.2; NaHCO₃, 24.9; KH₂ PO₄, 1.2; glucose, 11.1; EDTA, 0.023;gassed with 95% O₂ ; 2/5% CO₂ ; pH 7.4. The bladder is opened and thencut into strips 1-2 mm in width and 7-10 mm in length. The strips aresubsequently suspended in a 10 mL tissue bath under an initial restingtension of 1.5 g. The strips are held in place by two surgical clips oneof which is attached to fixed hook while the other is attached to anisometric force transducer. The preparations, which usually exhibitsmall spontaneous contractions, are allowed to recover for a period of 1hour prior to a challenge with 0.1 μM carbachol. The carbachol is thenwashed out and the tissue allowed to relax to its resting level ofactivity. Following 1 further 30 min period of recovery an additional 15mM KCl are introduced into the tissue bath. This increase in KClconcentration results in a large increase in the amplitude ofspontaneous contractions (and initiation of contractions in previouslyquiescent strips) superimposed upon a small increase in basal tone.Following stabilization of this enhanced level of contractile activity,incremenlal increases in the concentration of test compound or vehicleare introduced into the tissue bath. Contractile activity is measuredfor each compound or vehicle concentration during the last min of a 30min challenge.

Isometric force developed by the bladder strips is measured using aconcentration required to elicit 50% inhibition of pre-drug contractileactivity (IC₅₀ concentration) is calculated from thisconcentration-response curve. The maximum percentage inhibition ofcontractile activity evoked by a test compound is also recorded forconcentrations of test compound<or equal to 30 μM.

The results of this study are shown in Table I.

                  TABLE I                                                         ______________________________________                                        Inhibition of Contractions in Isolated Rat Bladder Strips                                                 Inhibition of Force                               Compound  n        IC.sub.50                                                                              (%) at (x) μM                                  ______________________________________                                        Example 1 6        0.056 μM                                                                            --                                                Example 4 3        2.3 μM                                                  Example 5 3        --       38% (30 μM)                                    Example 9 4        --       22% (30 μM)                                    Example 11                                                                              4        --       28% (30 μM)                                    ______________________________________                                    

Hence, the compounds of this invention have a pronounced effect onsmooth muscle contractility and are useful in the treatment of urinaryincontinence, irritable bladder and bowel disease, asthma, hypertension,stroke, and similar diseases as mentioned above, which are amenable totreatment with potassium channel activating compounds by administration,orally, parenterally, or by aspiration to a patient in need thereof.

What is claimed is:
 1. A compound of the formula: ##STR10## wherein: R₁is hydrogen, C₁₋₁₀ straight or branched chain alkyl, C₃₋₁₀ cyclic orbicyclic alkyl, alkanoyl of 2 to 7 carbon atoms, alkylsulfonyl of 1 to 7carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms;R₂ ishydrogen, C₁₋₁₀ straight or branched chain alkyl or C₃₋₁₀ cyclic orbicyclic alkyl; A is selected from the following: ##STR11## wherein: R₉is hydrogen, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆perfluoroalkoxy, amino, C₁₋₁₂ mono-or dialkylamino, C₁₋₆alkylsulfonamido, C₁₋₆ alkylcarboxamido, nitro, cyano, carboxyl, chloro,bromo, fluoro, iodo; n is an integer from 0 to 6; R₃ and R₄ are,independent from each other, hydrogen, C₁₋₁₀ straight or branched chainalkyl, or C₃₋₁₀ cyclic or bicyclic alkyl; C₁₋₁₀ perfluoro alkyl, C₁₋₁₀hydroxyalkyl, C₁₋₁₀ alkoxyalkyl, fluoro; or, when taken together, form aspirocyclic ring containing a total of 3-7 carbon atoms; R₅ and R₆,independent from each other, are selected from the following: cyano,nitro, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆perfluoroalkoxy, amino, C₁₋₁₂ mono- or dialkylamino, sulfonamide, C₁₋₆alkylsulfonamido, C₆₋₁₂ arylsulfonamido, C₁₋₆ alkylcarboxamido, C₆₋₁₂arylcarboxamido, C₁₋₆ alkylsulfonyl, C₁₋₆ perfluoroalkylsulfonyl, C₆₋₁₂arylsulfonyl, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl,carboalkoxy, hydroxyl, or hydrogen;or a pharmaceutically acceptable saltthereof.
 2. A compound of claim 1, in which A is selected from thefollowing: ##STR12## wherein: n=0;R₃ and R₄ are, independent from eachother, hydrogen, C₁₋₁₀ straight or branched chain alkyl, C₁₋₁₀ perfluoroalkyl, C₁₋₁₀ hydroxyalkyl or fluoro; R₅ and R₆, independent from eachother, are selected from the following: cyano, nitro, C₁₋₆ alkyl, C₁₋₆perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆ perfluoroalkoxy, amino, chloro, bromo,fluoro, iodo, carboxyl, carboalkoxy, hydroxyl, hydrogen;or apharmaceutically acceptable salt thereof.
 3. A method for reducing theadverse effects of smooth muscle contractions which comprisesadministering, orally or parenterally, to a patient in need thereof, acompound of the formula: ##STR13## wherein: R₁ is hydrogen, C₁₋₁₀straight or branched chain alkyl, C₃₋₁₀ cyclic or bicyclic alkyl,alkanoyl of 2 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms,aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms,arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbonatoms or arylalkylsulfonyl of 7 to 12 carbon atoms;R₂ is hydrogen, C₁₋₁₀straight or branched chain alkyl or C₃₋₁₀ cyclic or bicyclic alkyl; A isselected from the following: ##STR14## wherein: R₉ is hydrogen, C₁₋₆alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆ perfluoroalkoxy, amino,C₁₋₁₂ mono-or dialkylamino, C₁₋₆ alkylsulfonamido, C₁₋₆alkylcarboxamido, nitro, cyano, carboxyl, chloro, bromo, fluoro, iodo; nis an integer from 0 to 6; R₃ and R₄ are, independent from each other,hydrogen, C₁₋₁₀ straight or branched chain alkyl, or C₃₋₁₀ cyclic orbicyclic alkyl; C₁₋₁₀ perfluoro alkyl, C 1-10 hydroxyalkyl, C₁₋₁₀alkoxyalkyl, fluoro; or, when taken together, form a spirocyclic ringcontaining a total of 3-7 carbon atoms; R₅ and R₆, independent from eachother, are selected from the following: cyano, nitro, C₁₋₆ alkyl, C₁₋₆perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆ perfluoroalkoxy, amino, C₁ -12 mono-ordialkylamino, sulfonamide, C₁₋₆ alkylsulfonamido, C₆₋₁₂ arylsulfonamido,C₁₋₆ alkylcarboxamido, C₆₋₁₂ arylcarboxamido, C₁₋₆ alkylsulfonyl, C₁₋₆perfluoroalkylsulfonyl, C₆₋₁₂ arylsulfonyl, chloro, bromo, fluoro, iodo,1-imidazolyl, carboxyl, carboalkoxy, hydroxyl, or hydrogen;or apharmaceutically acceptable salt thereof.
 4. The compound of claim 1which is3-(5-bromo-pyridin-3-ylamino)-4-(1-phenyl-ethylamino)-cyclobut-3-ene-1,2-dione.5. The compound of claim 1 which is3-(1-phenyl-ethylamino)-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione.6. The method of claim 2 in which the smooth muscle adverselycontracting causes urinary incontinence.
 7. The method of claim 2 inwhich the smooth muscle adversely contracting causes irritable bowelsyndrome.